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N-Butyl-2-cyanoacrylate-based injectable and in situ-forming implants for efficient intratumoral chemotherapy.

ABSTRACT: The local delivery of chemotherapeutic drugs to tumor sites is an effective approach for achieving therapeutic drug concentrations in solid tumors. Injectable implants with the ability to form in situ represent one of the most promising technologies for intratumoral chemotherapy. However, many issues must be resolved before these implants can be applied in clinical practice. Herein, we report a novel injectable in situ-forming implant system composed of n-butyl-2-cyanoacrylate (NBCA) and ethyl oleate, and the sol-gel phase transition is activated by anions in body fluids or blood. This newly developed injectable NBCA ethyl oleate implant (INEI) is biodegradable, biocompatible, and non-toxic. INEI solidifies in several seconds after exposure to body fluids or blood, and the implant's in vivo degradation time can be controlled. In addition, the pore sizes formed by the polymerization of NBCA can be decreased by increasing the NBCA concentration in the implants. Therefore, the drug retention/release time can be adjusted from a few weeks to several months by changing the concentration of NBCA in the implant formulation. Anti-tumor experiments in animal models showed that the average growth inhibition rate of xenografted human breast cancer cells by the paclitaxel-loaded INEI (40% NBCA) was 80%, and they also indicated that tumors in some of the mice were completely eliminated by just a single dosage injection. For the epirubicin-loaded INEI (50% NBCA), the average growth inhibition rate of xenografted human liver cancer cells was 58%. Thus, the chemotherapeutic drug-loaded INEIs exhibited excellent therapeutic efficacy for local chemotherapy.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8240990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Ultrasound-guided intratumoral delivery of doxorubicin from in situ forming implants in a hepatocellular carcinoma model.

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Model simulation and experimental validation of intratumoral chemotherapy using multiple polymer implants.

Project description:Radiofrequency ablation has emerged as a minimally invasive option for liver cancer treatment, but local tumor recurrence is common. To eliminate residual tumor cells in the ablated tumor, biodegradable polymer millirods have been designed for local drug (e.g., doxorubicin) delivery. A limitation of this method has been the extent of drug penetration into the tumor (<5 mm), especially in the peripheral tumor rim where thermal ablation is less effective. To provide drug concentration above the therapeutic level as needed throughout a large tumor, implant strategies with multiple millirods were devised using a computational model. This dynamic, 3-D mass balance model of drug distribution in tissue was used to simulate the consequences of various numbers of implants in different locations. Experimental testing of model predictions was performed in a rabbit VX2 carcinoma model. This study demonstrates the value of multiple implants to provide therapeutic drug levels in large ablated tumors.

| S-EPMC5565878 | biostudies-other

Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

Project description:One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phantoms, and the constructs were treated daily for 14 days with ultrasound at 2.2 W/cm2 for 10 min. The 2D distribution of fluorescein within the phantoms was quantified using fluorescence imaging. Implants receiving ultrasound irradiation showed a 1.7-5.6 fold increase (p < 0.05) in fluorescence intensity and penetration distance, with the maximum increase observed 5 days post-implantation. However, this evidence was not seen when the same experiment was also carried out in phosphate buffer saline (pH 7.4). Results suggest an active role of ultrasound in local molecular transport in the phantom. An increase of fluorescein release and penetration depth in phantoms can be accomplished through brief application of ultrasound. This simple technique offers an opportunity to eventually enhance the therapeutic efficacy and broaden the application of local drug delivery systems.

| S-EPMC5693652 | biostudies-literature

In situ forming implants exposed to ultrasound enhance therapeutic efficacy in subcutaneous murine tumors.

Project description:In situ forming implants (ISFIs) allow for a high initial intratumoral concentration and sustained release of the chemotherapeutic. However, clinical translation is impeded primarily due to limited drug penetration from the tumor/boundary interface and poor intratumoral drug retention. Therapeutic ultrasound (TUS) has become a popular approach for improving drug penetration of transdermal devices and increasing cellular uptake of nanoparticles. These effects are driven by the mechanical and thermal bioeffects associated with TUS. In this study, we characterize the released drug penetration, retention, and overall therapeutic response when exposing ISFI to the combination of the mechanical and thermal effects of TUS (C-TUS). ISFIs were intratumorally injected into subcutaneous murine tumors then exposed to C-TUS (exposure: 5 min, duty factor: 0.33, frequency: 3 MHz, intensity: 2.2 W/cm2, pulse duration: 2 ms, pulse repetition frequency: 165 Hz, effective radiating area: 5 cm2, energy delivered: 896 J, time average intensity: 0.88 W/cm2). Tumors treated with the combination of ISFI + C-TUS demonstrated a 2.5-fold increase in maximum drug penetration and a 3-fold increase in drug retention at 5- and 8-days post-injection, respectively, compared to ISFIs without TUS exposure. These improvements in drug penetration and retention translated into an enhanced therapeutic response. Mice treated with ISFI + C-TUS showed a 62.6% reduction in tumor progression, a 50.0% increase in median survival time, and a 26.6% increase in necrotic percentage compared to ISFIs without TUS exposure. Combining intratumoral ISFIs with TUS may be beneficial for addressing some long-standing challenges with local drug delivery in cancer treatment and may serve as a viable noninvasive method to improve the poor clinical success of local drug delivery systems.

| S-EPMC7725358 | biostudies-literature

N-butyl-2-cyanoacrylate, iso-amyl-2-cyanoacrylate and hypertonic glucose with 72% chromated glycerin in gastric varices.

Project description:AimTo compare n-butyl-2-cyanoacrylate, iso-amyl-2-cyanoacrylate and a mixture of 72% chromated glycerin with hypertonic glucose solution in management of gastric varices.MethodsNinety patients with gastric varices presented to Endoscopy Unit of Ain Shams University Hospital were included. They were randomly allocated into three groups; each group included 30 patients treated with intravariceal sclerosant injections in biweekly sessions till complete obturation of gastric varices; Group I (n-butyl-2-cyanoacrylate; Histoacryl(®)), Group II (iso-amyl-2-cyanoacrylate; Amcrylate(®)) and Group III (mixture of 72% chromated glycerin; Scleremo(®) with glucose solution 25%). All the procedures were performed electively without active bleeding. Recruited patients were followed up for 3 mo.Results26% of Scleremo group had bleeding during puncture vs 3.3% in each of the other two groups with significant difference, (P < 0.05). None of Scleremo group had needle obstruction vs 13.3% in each of the other two groups with no significant difference, (P > 0.05). Rebleeding occurred in 13.3% of Histoacryl and Amcrylate groups vs 0% in Scleremo group with no significant difference. The in hospital mortality was 6.6% in both Histoacryl and Amcrylate groups, while it was 0% in Scleremo group with no significant difference. In the first and second sessions, the amount of Scleremo needed for obturation was significantly high, while the amount of Histoacryl was significantly low. Scleremo was the less costly of the two treatments.ConclusionAll used sclerosant substances showed efficacy and success in management of gastric varices with no significant differences except in total amount, cost and bleeding during puncture.

| S-EPMC4400631 | biostudies-literature

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